Review
Depression and Alzheimer's disease: Neurobiological links and common pharmacological targets

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Abstract

Depression is one of the most prevalent and life-threatening forms of mental illnesses, whereas Alzheimer's disease is a neurodegenerative disorder that affects more than 37 million people worldwide. Recent evidence suggests a strong relationship between depression and Alzheimer's disease. A lifetime history of major depression has been considered as a risk factor for later development of Alzheimer's disease. The presence of depressive symptoms can affect the conversion of mild cognitive impairment into Alzheimer's disease. Neuritic plaques and neurofibrillary tangles, the two major hallmarks of Alzheimer's disease brain, are more pronounced in the brains of Alzheimer's disease patients with comorbid depression as compared with Alzheimer's disease patients without depression. On the other hand, neurodegenerative phenomena have been observed in different brain regions of patients with a history of depression. Recent evidence suggests that molecular mechanisms and cascades that underlie the pathogenesis of major depression, such as chronic inflammation and hyperactivation of hypothalamic–pituitary–adrenal (HPA) axis, are also involved in the pathogenesis of Alzheimer's disease. In particular, a specific impairment in the signaling of some neurotrophins such as transforming-growth-factor β1 (TGF-β1) and brain-derived neurotrophic factor (BDNF) has been observed both in depression and Alzheimer's disease. In the present review we will examine the evidence on the common molecular pathways between depression and Alzheimer's disease and we will discuss these pathways as new pharmacological targets for the treatment of both major depression and Alzheimer's disease.

Introduction

Depression is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Estimates of prevalence range from 5 to 20% of the general population, when people with mild depressive episodes are included (Fava and Kendler, 2000, Kessler et al., 2005). Depression is associated with significant disability (Murray and Lopez, 1997) and with excess mortality (Cuijpers and Smit, 2002) particularly from cardiovascular disease (Rivelli and Jiang, 2007).

Current antidepressant drugs, which are directed against monoaminergic systems, provide a useful therapeutic tool, but approximately 30% of depressed patients failed to respond to these drugs and antidepressants produce remission only in 30% of patients. This can be explained by the fact that the pathophysiology of depression has not been completely elucidated, and treatments have been developed following the “monoaminergic hypothesis” of depression without taking into account other mechanisms involved in the pathophysiology of the disorder. The identification of these mechanisms represents a fundamental step for the identification of new targets and the design of new antidepressant drugs. Recent studies suggest that factors other than monoamine deficiency or imbalances between various neurotransmitter systems must be considered when describing the neurobiological basis of major depression, such as alterations in mechanisms to resilience to stress, reduced synaptic plasticity, impaired adult hippocampal neurogenesis and neurodegenerative phenomena in the hippocampus (Krishnan and Nestler, 2008).

Neurodegeneration is also the main histopathological feature of Alzheimer's disease, a devastating disorder affecting more than 37 million people worldwide. It is mainly characterized by memory loss, with disoriented behaviour and impairments in language, comprehension, and spatial skills. Neuropsychiatric symptoms, such as depression, psychosis and agitation are also frequent in people with Alzheimer's disease, and are a common precipitant of institutional care (Ballard et al., 2008). Current drugs for Alzheimer's disease are only symptomatic, but do not interfere with the underlying pathogenic mechanisms of the disease (Klafki et al., 2006). Therefore, recent efforts in Alzheimer's disease research are now directed to the identification of new molecular targets for the development of disease-modifying drugs able to counteract the degenerative processes and the resulting memory loss in Alzheimer's disease patients.

Alzheimer's disease is characterized by the presence of ß-amyloid in the senile plaques, intracellular aggregates of tau protein in the neurofibrillary tangles, and progressive neuronal loss (Hardy and Selkoe, 2002). Genetic studies and evidence from animal models support a primary role for ß-amyloid in the cascade of events which leads to neuronal death in Alzheimer's disease brain (Hardy and Selkoe, 2002). Oligomeric species composed of aggregated ß-amyloid are believed to exert toxic effects on synaptic and cellular functions, finally leading to neurodegeneration (Cerpa et al., 2008). Different mechanisms have been proposed to explain ß-amyloid neurotoxicity, such as oxidative stress (Butterfield et al., 2007), amplification of N-methyl-d-aspartate (NMDA) toxicity (Hynd et al., 2004), cell cycle activation in differentiated neurons (Giovanni et al., 1999, Copani et al., 1999, Herrup et al., 2004, Copani et al., 2007), and finally the sustained loss of the canonical Wnt pathway, a signalling pathway essential for maintaining neuronal homeostasis (Caricasole et al., 2004, Inestrosa et al., 2007).

Recent evidence, from epidemiology to neurobiology, suggests a strong relationship between depression and dementia. For different years depression and dementia have been considered completely distinct clinical entities. The term “pseudodementia” is used to define a clinical picture characterized by depression associated with cognitive impairment and responsiveness to antidepressant treatment, as opposed to depression as an early symptom of dementia, which is instead unresponsive to antidepressants (Gualtieri and Johnson, 2008). Recent evidence suggests that depression can act as a risk factor for dementia, in particular Alzheimer's disease, and, most importantly, common pathophysiological mechanisms between these two diseases have been identified, which might explain the progression from depression to Alzheimer's disease (Fig. 1). In the present review we will examine this evidence, focusing on the common molecular pathways as new pharmacological targets for the treatment of both depression and Alzheimer's disease.

Section snippets

The connection between depression and dementia: epidemiological evidence

Different studies suggest that depressive disorder is associated with increased risk of developing cognitive dysfunction (Kessing, 1998, Castaneda et al., 2008) and eventually dementia, in particular Alzheimer's disease (Geerlings et al., 2000, Ownby et al., 2006). Several groups have examined the temporal relationship between depression and Alzheimer's disease to understand whether depression is simply a prodromal symptom of Alzheimer's disease which precedes the onset of cognitive deficits,

Stress and dysfunction of the hypothalamic–pituitary–adrenal axis

Epidemiological evidence supports a role for stress as a risk factor both for depression (Pittenger and Duman, 2008) and Alzheimer's disease (Bao et al., 2008, Simard et al., 2009). Several studies clearly show that chronic exposure to stress and stressful life events may lead to the development of major depression (Czéh and Lucassen, 2007, Kendler et al., 1999, van Praag, 2004, Charney and Manji, 2004, Pariante, 2003), and that elderly individuals prone to psychological distress are more

Conclusion

In the present review we have examined recent evidence on the common molecular mechanisms and cascades between depression and Alzheimer's disease. The above short review did not intend to cover the vast amount of data in this field.

According to the discussed data we suggest that hyperactivation of HPA axis, chronic inflammation and deficit of neurotrophin signaling can be considered as common pathophysiological mechanisms between depression and Alzheimer's disease (Fig. 1) and are potential new

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